Elucidation of the type of cell death at the onset of non-alcoholic steatohepatitis (NASH)

Tsurusaki S1,2, Matsuda M1, Shimizu S3, Nakano H4, Miyajima A2 and Tanaka M1,2

  1. National Center for Global Health and Medicine, Tokyo, Japan.
  2. Institute for Quantitative Biology, The University of Tokyo, Tokyo, Japan.
  3. Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
  4. Toho University School of Medicine, Tokyo, Japan.

Non-alcoholic steatohepatitis (NASH) is a liver disease with which the number of patients has recently increased. Although the pathogenesis of NASH is still unclear, hepatic cell death triggered by abnormal accumulation of fat is considered as an etiology of NASH. In general, the types of cell death have been classified into apoptosis and necrosis. However, recent accumulating evidences about the new type of cell death "programed necrosis" have highlighted the role and significance of multiple types of cell death in human diseases. In this study, we aimed to identify the type of hepatic cell death involved in the initial onset of NASH. To address the issue, we used choline-deficient, ethionine-supplemented diet (CDE diet) model, which is a murine model of NASH. By monitoring the serum alanine aminotransferase (ALT) levels as a liver damage marker and the type of cell death in the progression of NASH, we found that massive hepatic cell death accompanied by apoptotic and necrotic hepatocytes was induced two days after feeding of CDE diet. To further investigate the type of cell death triggering the onset of NASH, we tested the inhibition of specific type of cell death by using chemical inhibitors or genetically modified mice. Consequently, ferroptosis inhibitors dramatically suppressed the onset of hepatic cell death in CDE-induced liver injury, suggesting that ferroptosis is a crucial cell death and a promising target for the pathogenesis and treatment of NASH.